Sex-related differences in presentation, treatment, and outcomes of Asian patients with atrial fibrillation: a report from the prospective APHRS-AF Registry

We aimed to investigate the sex-related differences in the clinical course of patients with Atrial Fibrillation (AF) enrolled in the Asia–Pacific-Heart-Rhythm-Society Registry. Logistic regression was utilized to investigate the relationship between sex and oral anticoagulant, rhythm control strategies and the 1-year chance to maintain sinus rhythm. Cox-regression was utilized to assess the 1-year risk of all-cause, and cardiovascular death, thromboembolic events, acute coronary syndrome, heart failure, and major bleeding. In the whole cohort (4121 patients, 69 ± 12 years,34.3% female), females had different cardiovascular risk factors, clinical manifestations, and disease perceptions than men, with more advanced age (72 ± 11 vs 67 ± 12 years, p < 0.001) and dyslipidemia (36.7% vs 41.7%, p = 0.002). Coronary artery disease was more prevalent in males (21.1% vs 16.1%, p < 0.001) as well as the use of antiplatelet drugs. Females had a higher use of oral anticoagulant (84.9% vs 81.3%, p = 0.004) but this difference was non-significant after adjustment for confounders. On multivariable analyses, females were less often treated with rhythm control strategies (Odds Ratio [OR] 0.44,95% Confidence Interval [CI] 0.38–0.51) and were less likely to maintain sinus rhythm (OR 0.27, 95% CI 0.22–0.34) compared to males. Cox-regressions analysis showed no sex-related differences for the risk of death, cardiovascular, and bleeding. The clinical management of Asian AF patients should consider several sex-related differences.

Classification of AF-related symptoms was performed according to the EHRA score 14 as follows: EHRA I, no symptoms; EHRA II, mild symptoms (normal daily activity not affected); EHRA III, severe symptoms (normal daily activity affected); EHRA IV, disabling symptoms (normal daily activity discontinued).
EHRA score considers symptoms attributable to AF and reverse or reduce upon restoration of sinus rhythm or with effective rate control and it was determined by recruiting sites.
EuroQoL is a well validated questionnaire utilized to evaluate the quality of life, that consists of five dimensions (mobility, self-care, usual activities, pain/discomfort and anxiety/depression) with five possible levels for each dimension (no problems, slight problems, moderate problems, severe problems and extreme problems).As previously reported, the answers provided by patients at baseline were utilized to generate a single numeric value for each domain that inversely related with the quality of life (highest value correspond to the worst quality of life) 15 .

Rhythm control definitions
After the enrolment, all patients who received a rhythm control intervention such as electrical or pharmacological cardioversion, catheter ablation, or were prescribed an antiarrhythmic drug (Class Ia, Class Ic, Class III), were included in the 'rhythm control' group.All the other patients were considered as treated with rate control strategies.

Statistical analysis
The distribution of linear variables was assessed by the Kolmogorov-Smirnov test.Continuous variables with normal distribution were expressed as mean ± standard deviation (SD) and compared by Student's T test.Categorical variables were reported as counts and percentages and were compared with the χ 2 test.
Logistic regression analysis was used to calculate Odds Ratios (OR) with relative 95% Confidence Interval (95% CI) for (i) oral anticoagulant (OAC) prescription, (ii) Vitamin K antagonist (VKA) use, (iii) rhythm control interventions (pharmacological and electrical cardioversion, and catheter ablation), and (iv) 1-year maintenance of sinus rhythm in patients with rhythm control strategies.
The incidence rate of adverse events (All-cause death, cardiovascular death, thromboembolic events, acute coronary syndrome or significant coronary artery disease requiring percutaneous coronary intervention (ACS/ PCI), new or worsening of a preexisting heart failure, and major bleeding) was calculated as the number of events / total person-years ratio and reported as incidence for 100 persons/year with relative 95% CI.The 1-year risks of adverse events were compared between males and females.Cox proportional hazards regression time to the first event analysis was used to calculate the unadjusted and adjusted relative hazard ratios (HRs) and 95% CI of adverse events.All the multivariable Cox regression analyses were adjusted for the following covariates: age, CHA 2 DS 2 -VASc or HAS-BLED risk scores, OAC, chronic kidney disease (CKD), paroxysmal AF, cancer, dementia, dyslipidemia, and chronic obstructive pulmonary disease (COPD).Proportional hazard assumptions were checked with the Schoenfeld residuals test.Patients without available data to calculate the clinical scores, or to investigate the antithrombotic treatment, the rhythm or rate management, or without follow-up were excluded from the analysis.All tests were 2-tailed, and analyses were performed using computer software packages (SPSS-25.0,SPSS Inc., Chicago, IL).A p-value < 0.05 was considered as statistically significant.

Results
Of the 4666 patients with AF enrolled in the APHRS registry, 2 patients died before discharge, 458 were lost to follow-up or withdrawn their informed consent and 85 had an unknown follow-up status.Thus, in the final analysis, we considered 4121 patients with available follow-up, of whom 1423 (34.5%) were females (mean age 71.5 ± 11.2 years) and 2698 (65.5%) were males (mean age 67.0 ± 11.1 years).

Clinical characteristics
Females were older, with a higher prevalence of dyslipidemia, dementia and anemia, a lower prevalence of coronary artery disease (CAD) and COPD, and were more frequently treated with statins, digoxin, diuretics, and calcium antagonist than males (Table 1).The most frequent AF patterns were paroxysmal in females and persistent in males.Female sex was associated with a higher prevalence of severe or disabling symptoms (EHRA score III or IV), mainly represented by palpitations and chest pain, and worse quality of life, as shown by the higher EuroQoL scores in all five domains (Table 1).

Antithrombotic management
Females had higher mean CHA 2 DS 2 -VASc and HAS-BLED risk scores, greater use of OAC, and were less treated with antiplatelets drugs compared to males (Table 1).In anticoagulated patients, no significant sex-related differences were found for the relative prevalence of VKA and non-vitamin K antagonist oral anticoagulants (NOAC) use.The main reasons associated with the lack of any OAC therapy were due to anemia, frequent falls, and dementia in females, and a low thromboembolic risk score (CHA 2 DS 2 -VASc < 1) in males (Table 1).
Given the baseline higher prevalence of OAC use in females, we investigated this aspect using multivariate regression analysis (Fig. 1).The only factor independently associated with OAC use was higher CHA 2 DS 2 -VASc score, while paroxysmal AF, CKD, dementia, anemia and previous bleeding were associated with a lower OAC prescription.No significant associations between sex and OAC was found after adjustment for confounding factors (Fig. 1).
In our cohort, the most used OAC treatment was represented by NOAC and only 826 (24.3%) patients were treated with VKA.To investigate the presence of sex-related differences in OAC type, a multivariable logistic regression analysis showed age, CHA 2 DS 2 -VASc, CKD, and anemia were associated with a higher VKA use while paroxysmal AF and active cancer were associated with a lower VKA use.The lack of independent association between sex and VKA was confirmed also in this analysis (Supplementary Table 1).
In the rhythm control group, the procedures most used in males were electrical cardioversion and catheter ablation while females were more commonly managed with antiarrhythmic therapies and pharmacological cardioversion (Table 2).

Discussion
In this large prospective cohort of Asian patients with AF, our principal findings were as follows: (i) females had a different cardiovascular risk factor profile, more disabling symptoms, and worse quality of life; (ii) females were less treated with rhythm control strategies and had a lower maintenance of sinus rhythm; and (iii) females were not associated with a higher risk of thromboembolic events after adjustment for confounding factors.
The cardiovascular risk profile of females was characterized by advanced age and a high prevalence of dyslipidemia, whereas for males, there was more prevalent CAD and COPD.These findings are in contrast to the distinctive sex-related characteristics reported in the EORP-AF registry, in which CAD and COPD were more frequent in females while hypertension was in males 2 .Although the observational nature of these registries could itself warrant these differences, another possible explanation could be provided by the higher overall prevalence of dyslipidemia and the less effective cholesterol control achieved with statins reported in Asians compared to Western populations [16][17][18] .Hence, female sex, rather than a typical cardiovascular risk factor, represents a risk  modifier that increases the risk associated with other comorbidities, especially in older subjects where the protective role of female hormones is lacking 19 .Thus, the high prevalence of dyslipidemia in older Asian women with AF, rather than an occasional finding, could result from the interactions between advanced age, hormonal changes, and ethnic factors.
In our population, after adjustment for confounding factors, no significative sex-related differences were found for OAC or VKA use.This may reflect recent studies showing that NOAC introduction was associated with less bleeding in Asian women, resulting in the sex differences seen 20 .However, when analyzing the reasons behind the choice of not using any OAC, this was evident in males with low thrombotic risk, and in females by the presence of a frail phenotype characterized by anemia, frequent falls, and dementia.Having achieved the large OAC use in most of the high-risk patients with AF, the next challenging step will be to find the best sex-based approaches to optimize OAC adherence and to avoid interruptions or discontinuation.
Based on previous studies, AF-related symptoms have a higher disabling effect in women than in males, leading to their worse quality of life 2,3,10,21 .Nevertheless, the possible explanation for this worst symptomatic status may simply lie in women's older age, as well as rhythm control approaches utilized in our cohort.
The most recent guidelines for AF management, proposed by ESC 22 and then also adopted by APHRS 23 , introduced the concept of the integrated ABC (Atrial fibrillation Better Care) pathway by which the management of the symptoms should be done according to the patient-centered symptom-directed decisions.Despite the impact of rhythm control strategy on mortality has been debated, but early rhythm control ameliorates AFrelated symptoms and improves quality of life in patients who maintain sinus rhythm 24,25 .In the present study, we found that women, notwithstanding being more symptomatic, were less frequently treated with rhythm control approaches.In particular, females were associated with a lower use of electrical cardioversion, and catheter ablation procedures, and a higher use of antiarrhythmics drugs and pharmacological cardioversion compared to males.This is in line with other studies performed both in Asian 26,27 and Western patients 3,21 .Of note, the different use of rhythm control strategies could also be related to the high rate of intra-and post-procedural complications, with the worse outcomes described in women [28][29][30] as well as the high prevalence of CAD that could have contraindicated the use of antiarrhythmic drugs in males.
The observational nature of this study does not allow us to further clarify these issues, but better compliance with international guidelines for AF symptom management, could help not only to equalize the access to rhythm control procedures between sexes but especially to investigate, in future studies, if the mechanisms behind the low chance to maintain the sinus rhythm in women is associated with less effective approaches or intrinsic factors.
Analyzing the clinical outcome after 1-year of follow-up, we found that the female sex was associated with a higher incidence rate of cardiovascular death and thromboembolic events compared to males, yet this difference was non-significative after adjustment for confounding factors.Several studies performed in Western populations showed that female sex is a strong risk factor for stroke and thromboembolism 4,31,32 .However, in recent years growing evidence suggests that this relationship may be less evident when considering Asian populations 8,9,33 .In a Japanese population of 7406 patients with AF (29.2% females), after 2-years follow-up, no significative difference was found for the risk of stroke or thromboembolism (OR 1.24, 95% CI 0.83-1.86) in females compared to males 8 .Nonetheless there was a mix of OAC and non-OAC users, which does not account for quality of anticoagulation control if on a VKA, or label-adherent dosing in case of NOACs.This finding was further confirmed in a Taiwanese cohort of 7920 patients (45.8% females) followed for 4.5 years 33 , in a Korean cohort of 10,846 patients (46.8% women) followed for 2.8 years 9 , and in a Chinese cohort of 6239 patients (41.3% females) followed for 2.8 years 34 .One large metanalysis of more than 990,000 patients, demonstrated that the risk of stroke in women changes accordingly with the different ethnic group and was the lowest in Asians 35 .
The mechanisms responsible for sex differences in determining the risk of stroke in different ethnic groups are unclear.What is emerging is that sex should be considered as a dynamic risk modification factor that changes its relationship with the risk of cardiovascular diseases over time and based on the coexistence of other cardiovascular risk factors 19 .If in young people female sex has a protective role, in older age, it enhances the effect of other cardiovascular risk factors.Furthermore, the female sex could interact not only with the traditional cardiovascular risk factors but also with the novel characters involved in the global cardiovascular burden, as represented by the social determinants of health and ethnic origin.

Limitations
Some limitations should be acknowledged when interpreting these results.First, this is a post-hoc analysis from an observational study, and caution should be used when generalizing our findings for due to the possible reduced power and presence of selection bias.Although we considered more than 88% of the initial cohort, the differences between the excluded and the included cohort, as well as the different prevalence of the two sexes in the final cohort, may have influenced the main analysis.The lack of exhaustive information regarding the type of catheter ablation intervention does not allow us to investigate the prevalence and the outcome associated with different types of procedures.Only 69.3% of the initial cohort have had an ECG attesting the rhythm after 1-year of follow-up and cannot be excluded that some patients may have had experienced a clinical silent AF paroxysm during the follow-up.Furthermore, no information is available about the time in therapeutic range in patients treated with VKA or about the dosage in those treated with NOAC, making it impossible to consider these factors in the survival analysis.Moreover, we had limited data on the impact of social determinants in this cohort, and further studies are needed to understand how gender-related factors and sex interact in determining the clinical phenotypes or the long-term outcomes of AF patients.Finally, the relatively small sample size, the short follow-up, and the small number of events could have affected the statistical power of our analysis missing to detect significant differences.

Figure 1 .
Figure 1.Logistic multivariate analysis for factors associated with oral anticoagulant use.

Figure 2 .
Figure 2. Logistic multivariate analysis for the factors associated with rhythm control strategies after the enrollment.

Figure 3 .
Figure 3. Logistic multivariate analysis for factors associated with the sinus rhythm maintenance after 1-year of follow-up.

Table 2 .
Rhythm control strategies in patients with atrial fibrillation according to sex.

Table 3 .
Incidence rates and Cox regression analyses for risk of primary and secondary outcomes according to sex.CI confidence interval, HR hazard ratio, CV cardiovascular, ACS/PCI acute coronary syndrome/ percutaneous coronary intervention, HF heart failure, AF atrial fibrillation, OAC oral anti-coagulant, CKD chronic kidney disease, COPD chronic obstructive pulmonary disease, Ref reference group.*Adjusted for: age, paroxysmal AF, CHA 2 DS 2 -VASc or HAS-BLED (for major bleeding), OAC, CKD, cancer, dementia, dyslipidemia, COPD.